Critical analysis on the use of cholecalciferol as a COVID-19 intervention: a narrative review

ABSTRACT BACKGROUND: The World Health Organization has declared that a pandemic situation exists in relation to the disease caused by the new coronavirus, COVID-19. So far, the absence of a vaccine against the new coronavirus has led people worldwide to seek various therapeutic alternatives, including use of cholecalciferol. DESIGN AND SETTING: Narrative review developed by a research group at a public university in Recife (PE), Brazil. METHODS: We searched the literature on the use of cholecalciferol for prevention or treatment of COVID-19, using the MEDLINE and LILACS databases, with the keywords “vitamin D”, “cholecalciferol”, “SARS-CoV-2”, “COVID-19” and “coronavirus”, from January 1, 2020, to June 10, 2020. Narrative reviews, cohort studies and ecological studies were selected. RESULTS: We retrieved 32 references, of which 8 were considered eligible for intensive review and critical analysis. These comprised five narrative reviews, two observational studies and one protocol proposal. Most of the studies selected reported positive effects from use of vitamin D for prevention or treatment of COVID-19. However, there was little quantitative data to assess the real impact of using this vitamin as an intervention against this disease. CONCLUSIONS: Current studies on vitamin D used for purposes other than bone health promotion cannot be taken as support to justify its use in a disease as recent as COVID-19. Studies of greater robustness, with higher levels of clinical evidence, need to be conducted. Rational use of this vitamin needs to be ensured, thereby minimizing the impacts on the patient and the public healthcare system.

This relates not to the intrinsic risk of the product but, rather, reflects flaws or errors within the process of using it that put users' safety at risk. Incidents with medications can result in physical, social or psychological damage to the patient, as well as contributing to longer hospital stay, which results in cost. These considerations also gain much greater weight in the context of the current pandemic. 12,13 Some studies have investigated the use of cholecalciferol as a therapeutic alternative for prevention or treatment of COVID- 19, but no reviews focusing on critical analysis of this use have yet been conducted.

OBJECTIVE
The objective of the current narrative review was to evaluate the proposition of using cholecalciferol for prevention or treatment of COVID-19 and the resulting implications.

METHODS
We conducted a review of the literature considering the period from January 1, 2020, to June 10, 2020. We used the MEDLINE database (via PubMed) and LILACS (via Virtual Health Library) to identify relevant articles from the starting point of a structured question, created in accordance with the acronym PICO (Population, Intervention, Comparator and Outcomes). The population was defined as "patients with a confirmed or probable diagnosis of COVID-19 infection" and the intervention considered was "vitamin D".
Because the analysis sought to find evidence about the use of a drug that would contribute to the clinical condition of the disease caused by the new coronavirus, terms that specified comparators, outcomes and types of study were not used. Different combinations of keywords and MeSH terms were used as search strategies to ensure a broad search strategy: "vitamin D", "cholecalciferol", "SARS-CoV-2", "COVID-19" and "coronavirus".
Firstly, the titles and abstracts of the references identified through the search strategy were screened, so that potentially eligible studies were preselected. Studies that were human trials, in English or Portuguese, in which immunological parameters in response to the viral infection caused by the new coronavirus were observed, were considered eligible. Animal studies, studies in languages other than Portuguese or English, letters, comments, reports, technical notes and editorial notes were excluded.
The articles thus selected were read in full, independently, by two authors. In cases of disagreement, a third reviewer was consulted. The following data were extracted: author, year of publication, country, study design, age of subjects (years on average), type of coronavirus, sample size, proportion of men (%), funding sources, intervention, comparator, outcomes (clinical, laboratory).
In the second stage, the methodological quality and the risk of bias in the text were fully assessed using the Joanna Briggs and STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) tools. 14,15

RESULTS
From the search in the databases, 32 references were identified.
After screening the titles and abstracts, eight studies were considered eligible for critical analysis. The search in LILACS using the keywords led to four results concerning the specific topic of interest, but these were excluded in accordance with the eligibility criteria, as described in Table 1.
The article selection process is detailed in Figure 1. In this process, out of the 32 records identified, only 23 remained after  Most of the studies included in this review were narrative reviews (n = 5), and there was also one protocol proposal. For these, it was not possible to apply any tool to make an evidence-based critical evaluation. The remaining two studies were observational: one of retrospective nature and the other, an ecological cohort.
Only these two studies were evaluated in relation to methodological quality and risk of bias. Despite a lack of robust quantitative data on vitamin D as an intervention against COVID-19, these two studies recommended its use.

Main findings
The  [24][25][26][27][28] Those authors further stated that, to reduce the risk of infection, it is recommended that people at risk of influenza and/or COVID-19 should consider taking 10,000 international units (IU)/day of vitamin D3 for a few weeks to rapidly increase their concentrations of 25(OH)D, followed by 5,000 IU/day. 17 Nevertheless, another narrative review, published by Hribar et al., 19 also suggested that daily supplementation of 2,000-5,000 IU/ day of vitamin D3, specifically for elderly people with Parkinson's disease, could offer additional protection against COVID-19. 19 Grant et al. also argued that, for the treatment of people infected with COVID-19, higher doses of vitamin D 3 might be useful. 17 Likewise, a narrative review published by Calder et al. 18 showed, among other conclusions, that supplementation above the recommended dose, but within the safety limits for specific nutrients such as vitamins C and D was necessary in order to increase the resistance to respiratory infections, such as those caused by  Although the authors of the narrative reviews emphasized that further studies were needed because of the current situation relating to the outbreak of COVID-19, it needs to be emphasized that, Therefore, the results from this study need to be interpreted cautiously. The authors themselves emphasized that the hypothesis towards which their study pointed would need to be taken forward and investigated using study designs of greater robustness.
The retrospective cohort study published by D' Avolio et al. 31 proposed that concentrations of 25-hydroxyvitamin D would be lower in patients with SARS-CoV-2 who were positive for C-reactive protein (CRP). 31 The study was conducted in Switzerland, among 1,484 patients of both sexes and of ages ranging from 18 to 70 years.
However, although its design presented greater strength of evidence than the studies cited above (observational study and narrative reviews), no inclusion/exclusion criteria were established among the study groups. Thus, the only variables assessed were sex and age.
Consequently, the profile of the patients seen remained unclear with regard to disease severity, and the description of the study subjects did not allow verification of whether the populations were comparable.
Considering that most complications and deaths due to  have been reported among elderly patients with evidence of underlying diseases, such as cardiovascular, pulmonary or kidney disease, or cancer, the limiting criteria established in this study increased the risk of bias. 1 Additionally, it needs to be considered that vitamin D levels may also vary according to hormonal, genetic and nutritional factors. 33 Thus, the analysis did not allow identification of whether vitamin D deficiency was an underlying illness rather than the cause.
Confounding factors would therefore possibly arise, especially due to the lack of information about the population at the baseline, which could influence the direction of the results. Although the authors considered some of these factors, they did not describe the strategies used to deal with confounding factors.
Therefore, it becomes evident that further research needs to be conducted, especially given that the amount of supplemental vitamin D to be administered continues to be a matter for debate in the 21 st century, even in relation to well-established diseases such as those linked to mineral metabolism. The discussion becomes even more complex with regard to a disease as recent as that caused by the new coronavirus. 11,34 Thus, the urgent need to combat the current pandemic must not override the need to make rational use of medicines. In the case of cholecalciferol, several studies have suggested that vitamin D intoxication may occur when doses greater than 10,000 IU are administered daily, for periods lasting from several months to some years. 35 Therefore, building up a toxic dose of vitamin D through supplementation is a real possibility. This can lead to consequences such as hypercalcemia and hypercalciuria, with consequent risks of renal failure, seizures and death. 10,36,37 In Brazil, medications are responsible for more than 52% of intoxications in this country, and 15% to 20% of hospital budgets are spent on treatment of complications resulting from them. 38,39 Considering that public healthcare systems worldwide are becoming depleted through the current pandemic, it is essential that events caused by irrational use of medicines should be avoided and that extrapolation of their use to form treatments for COVID-19 should be discussed better and be based on well-supported clinical studies.

Strengths and limitations
The articles included in this review generated heterogeneous data because of the diversity in the design of the studies (five narrative reviews, two observational studies and one treatment protocol).
The main limitation of this review was the lack of tools for methodological assessment of narrative reviews. Nonetheless, these reviews were maintained in the present study in view of the scarcity of data on the use of vitamin D for treatment of COVID- 19. The studies lacked high levels of scientific evidence to support their conclusions.
As far as we know, this was the first study to critically review and evaluate the use of vitamin D as an intervention tool for treatment of COVID-19. Thus, this study is of great value for safe decision-making regarding rational use of this medicine in the context of the current pandemic.

CONCLUSIONS
In the studies included through the systematic search of this review, no robust and conclusive evidence regarding the effectiveness of the use of vitamin D for prevention or treatment of COVID-19 was identified. The studies analyzed presented limitations regarding their designs and methodologies, which implied high risk of bias.
Thus, the current studies on use of vitamin D for purposes other than bone health promotion cannot be taken as support for justifying its use in a disease as recent as COVID-19. Hence, further studies with greater robustness of clinical evidence need to be conducted. Through this, rational use of this vitamin will be ensured and the impacts on patients and the public healthcare system will be minimized.